Clinical pharmacokinetics of cyclophosphamide and metabolites with and without SR-2508

The pharmacokinetics of cyclophosphamide (CP) and several important metabolites was studied in detail in six patients receiving CP alone and with a radio- and chemosensitizing agent, SR-2508. CP at 1000 mg/m2 was either infused in 20 min alone or given 2 h before an infusion of SR-2508 at 5 g/m2 ove...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 1994-12, Vol.54 (24), p.6421-6429
Hauptverfasser: CHAN, K. K, HONG, P. S, TUTSCH, K, TRUMP, D. L
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container_issue 24
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creator CHAN, K. K
HONG, P. S
TUTSCH, K
TRUMP, D. L
description The pharmacokinetics of cyclophosphamide (CP) and several important metabolites was studied in detail in six patients receiving CP alone and with a radio- and chemosensitizing agent, SR-2508. CP at 1000 mg/m2 was either infused in 20 min alone or given 2 h before an infusion of SR-2508 at 5 g/m2 over 20 min, both separated by 3 weeks, to the same patients in a randomized fashion. Plasma and 24-h urinary levels of CP and four metabolites: [4-hydroxycyclophosphamide (4-OH CP), phosphoramide mustard (PM), chloroethyl oxazolidin-2-one, and alcophosphamide] were monitored by a gas chromatographic-mass spectrometric-stable isotope dilution assay. CP plasma levels were found to decline monoexponentially with the appearance of transient saturation kinetics in some and a mean t1/2 of 5.2 h for patients treated with CP alone. Plasma 4-OH CP levels showed a mean peak concentration of 2.4 microM and declined approximately in parallel to those of CP. The major circulating metabolite was found to be PM with a mean peak concentration of 40 microM and a terminal t1/2 of 15 h. The mean area under the plasma concentration curve (AUC) ratios between metabolites and CP were: 4-OH CP, 0.0158; PM, 0.4518; and chloroethyl oxazolidin-2-one, 0.179 with alcophosphamide at low levels. No appreciable amount of nornitrogen mustard was detected. Mean urinary excretion was: CP, 10.8; 4-OH, CP, 0.5; PM, 39.0; alcophosphamide, 0.4; and chloroethyl oxazolidin-2-one, 3.0, all expressed as a percentage of CP dose. No statistically significant difference was detected in all standard pharmacokinetic parameters determined for both CP and metabolites between patients with CP alone and with SR 2508. Plasma 4-(p-nitrobenzyl)pyridine activity was found to correlate the closest with PM profiles, with respect to both standard pharmacokinetic parameters and AUC values. When plasma PM AUC values were plotted against AUC values of circulating 4-(p-nitrobenzyl)pyridine activity, a correlation coefficient of 0.859 (P < 0.001) was obtained. Together with the significant cytotoxicity of PM these data support a significant contribution of circulating PM in the antitumor effect of PM.
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K ; HONG, P. S ; TUTSCH, K ; TRUMP, D. L</creator><creatorcontrib>CHAN, K. K ; HONG, P. S ; TUTSCH, K ; TRUMP, D. L</creatorcontrib><description>The pharmacokinetics of cyclophosphamide (CP) and several important metabolites was studied in detail in six patients receiving CP alone and with a radio- and chemosensitizing agent, SR-2508. CP at 1000 mg/m2 was either infused in 20 min alone or given 2 h before an infusion of SR-2508 at 5 g/m2 over 20 min, both separated by 3 weeks, to the same patients in a randomized fashion. Plasma and 24-h urinary levels of CP and four metabolites: [4-hydroxycyclophosphamide (4-OH CP), phosphoramide mustard (PM), chloroethyl oxazolidin-2-one, and alcophosphamide] were monitored by a gas chromatographic-mass spectrometric-stable isotope dilution assay. CP plasma levels were found to decline monoexponentially with the appearance of transient saturation kinetics in some and a mean t1/2 of 5.2 h for patients treated with CP alone. Plasma 4-OH CP levels showed a mean peak concentration of 2.4 microM and declined approximately in parallel to those of CP. The major circulating metabolite was found to be PM with a mean peak concentration of 40 microM and a terminal t1/2 of 15 h. The mean area under the plasma concentration curve (AUC) ratios between metabolites and CP were: 4-OH CP, 0.0158; PM, 0.4518; and chloroethyl oxazolidin-2-one, 0.179 with alcophosphamide at low levels. No appreciable amount of nornitrogen mustard was detected. Mean urinary excretion was: CP, 10.8; 4-OH, CP, 0.5; PM, 39.0; alcophosphamide, 0.4; and chloroethyl oxazolidin-2-one, 3.0, all expressed as a percentage of CP dose. No statistically significant difference was detected in all standard pharmacokinetic parameters determined for both CP and metabolites between patients with CP alone and with SR 2508. Plasma 4-(p-nitrobenzyl)pyridine activity was found to correlate the closest with PM profiles, with respect to both standard pharmacokinetic parameters and AUC values. When plasma PM AUC values were plotted against AUC values of circulating 4-(p-nitrobenzyl)pyridine activity, a correlation coefficient of 0.859 (P &lt; 0.001) was obtained. Together with the significant cytotoxicity of PM these data support a significant contribution of circulating PM in the antitumor effect of PM.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>PMID: 7987837</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Antineoplastic agents ; Biological and medical sciences ; Chemotherapy ; Cyclophosphamide - analogs &amp; derivatives ; Cyclophosphamide - blood ; Cyclophosphamide - pharmacokinetics ; Cyclophosphamide - urine ; Etanidazole - pharmacokinetics ; Etanidazole - pharmacology ; Humans ; Medical sciences ; Pharmacology. 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L</creatorcontrib><title>Clinical pharmacokinetics of cyclophosphamide and metabolites with and without SR-2508</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>The pharmacokinetics of cyclophosphamide (CP) and several important metabolites was studied in detail in six patients receiving CP alone and with a radio- and chemosensitizing agent, SR-2508. CP at 1000 mg/m2 was either infused in 20 min alone or given 2 h before an infusion of SR-2508 at 5 g/m2 over 20 min, both separated by 3 weeks, to the same patients in a randomized fashion. Plasma and 24-h urinary levels of CP and four metabolites: [4-hydroxycyclophosphamide (4-OH CP), phosphoramide mustard (PM), chloroethyl oxazolidin-2-one, and alcophosphamide] were monitored by a gas chromatographic-mass spectrometric-stable isotope dilution assay. CP plasma levels were found to decline monoexponentially with the appearance of transient saturation kinetics in some and a mean t1/2 of 5.2 h for patients treated with CP alone. Plasma 4-OH CP levels showed a mean peak concentration of 2.4 microM and declined approximately in parallel to those of CP. The major circulating metabolite was found to be PM with a mean peak concentration of 40 microM and a terminal t1/2 of 15 h. The mean area under the plasma concentration curve (AUC) ratios between metabolites and CP were: 4-OH CP, 0.0158; PM, 0.4518; and chloroethyl oxazolidin-2-one, 0.179 with alcophosphamide at low levels. No appreciable amount of nornitrogen mustard was detected. Mean urinary excretion was: CP, 10.8; 4-OH, CP, 0.5; PM, 39.0; alcophosphamide, 0.4; and chloroethyl oxazolidin-2-one, 3.0, all expressed as a percentage of CP dose. No statistically significant difference was detected in all standard pharmacokinetic parameters determined for both CP and metabolites between patients with CP alone and with SR 2508. Plasma 4-(p-nitrobenzyl)pyridine activity was found to correlate the closest with PM profiles, with respect to both standard pharmacokinetic parameters and AUC values. When plasma PM AUC values were plotted against AUC values of circulating 4-(p-nitrobenzyl)pyridine activity, a correlation coefficient of 0.859 (P &lt; 0.001) was obtained. Together with the significant cytotoxicity of PM these data support a significant contribution of circulating PM in the antitumor effect of PM.</description><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Chemotherapy</subject><subject>Cyclophosphamide - analogs &amp; derivatives</subject><subject>Cyclophosphamide - blood</subject><subject>Cyclophosphamide - pharmacokinetics</subject><subject>Cyclophosphamide - urine</subject><subject>Etanidazole - pharmacokinetics</subject><subject>Etanidazole - pharmacology</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Pharmacology. 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L</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>19941215</creationdate><title>Clinical pharmacokinetics of cyclophosphamide and metabolites with and without SR-2508</title><author>CHAN, K. K ; HONG, P. S ; TUTSCH, K ; TRUMP, D. L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h269t-9ab11214bd774630c18e2e2cf17bc5087ca71a4deae82c914fa057b438c0474c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1994</creationdate><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Chemotherapy</topic><topic>Cyclophosphamide - analogs &amp; derivatives</topic><topic>Cyclophosphamide - blood</topic><topic>Cyclophosphamide - pharmacokinetics</topic><topic>Cyclophosphamide - urine</topic><topic>Etanidazole - pharmacokinetics</topic><topic>Etanidazole - pharmacology</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Phosphoramide Mustards - blood</topic><topic>Pyridines - blood</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>CHAN, K. K</creatorcontrib><creatorcontrib>HONG, P. S</creatorcontrib><creatorcontrib>TUTSCH, K</creatorcontrib><creatorcontrib>TRUMP, D. L</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>CHAN, K. K</au><au>HONG, P. S</au><au>TUTSCH, K</au><au>TRUMP, D. L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Clinical pharmacokinetics of cyclophosphamide and metabolites with and without SR-2508</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>1994-12-15</date><risdate>1994</risdate><volume>54</volume><issue>24</issue><spage>6421</spage><epage>6429</epage><pages>6421-6429</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>The pharmacokinetics of cyclophosphamide (CP) and several important metabolites was studied in detail in six patients receiving CP alone and with a radio- and chemosensitizing agent, SR-2508. CP at 1000 mg/m2 was either infused in 20 min alone or given 2 h before an infusion of SR-2508 at 5 g/m2 over 20 min, both separated by 3 weeks, to the same patients in a randomized fashion. Plasma and 24-h urinary levels of CP and four metabolites: [4-hydroxycyclophosphamide (4-OH CP), phosphoramide mustard (PM), chloroethyl oxazolidin-2-one, and alcophosphamide] were monitored by a gas chromatographic-mass spectrometric-stable isotope dilution assay. CP plasma levels were found to decline monoexponentially with the appearance of transient saturation kinetics in some and a mean t1/2 of 5.2 h for patients treated with CP alone. Plasma 4-OH CP levels showed a mean peak concentration of 2.4 microM and declined approximately in parallel to those of CP. The major circulating metabolite was found to be PM with a mean peak concentration of 40 microM and a terminal t1/2 of 15 h. The mean area under the plasma concentration curve (AUC) ratios between metabolites and CP were: 4-OH CP, 0.0158; PM, 0.4518; and chloroethyl oxazolidin-2-one, 0.179 with alcophosphamide at low levels. No appreciable amount of nornitrogen mustard was detected. Mean urinary excretion was: CP, 10.8; 4-OH, CP, 0.5; PM, 39.0; alcophosphamide, 0.4; and chloroethyl oxazolidin-2-one, 3.0, all expressed as a percentage of CP dose. No statistically significant difference was detected in all standard pharmacokinetic parameters determined for both CP and metabolites between patients with CP alone and with SR 2508. Plasma 4-(p-nitrobenzyl)pyridine activity was found to correlate the closest with PM profiles, with respect to both standard pharmacokinetic parameters and AUC values. When plasma PM AUC values were plotted against AUC values of circulating 4-(p-nitrobenzyl)pyridine activity, a correlation coefficient of 0.859 (P &lt; 0.001) was obtained. Together with the significant cytotoxicity of PM these data support a significant contribution of circulating PM in the antitumor effect of PM.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>7987837</pmid><tpages>9</tpages></addata></record>
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source MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
subjects Antineoplastic agents
Biological and medical sciences
Chemotherapy
Cyclophosphamide - analogs & derivatives
Cyclophosphamide - blood
Cyclophosphamide - pharmacokinetics
Cyclophosphamide - urine
Etanidazole - pharmacokinetics
Etanidazole - pharmacology
Humans
Medical sciences
Pharmacology. Drug treatments
Phosphoramide Mustards - blood
Pyridines - blood
Time Factors
title Clinical pharmacokinetics of cyclophosphamide and metabolites with and without SR-2508
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